Dibenzothiazepine derivatives

ABSTRACT

Compounds of the formula   WHEREIN EACH OF X1 and X2 is hydrogen or halogen; R1 is alkyl, haloalkyl, aralkyl or alkyl substituted with R3 in which R3 is amino, alkylamino, dialkylamino; and R2 is hydrogen, alkyl, haloalkyl, aralkyl or alkyl substituted with R3 in which R3 is the same meaning as defined above, provided that either R1 or R2 should be alkyl substituted with R3. These compounds possess potent antireserpinelike activity which makes them useful as an antidepressant.

United States Patet [72] Inventors Suminori Umio Kawani-shi; lkuo Ueda,Sakai, both of Japan [21] Appl. No. 722,169 [22) Filed Apr. 18, 1968[45] Patented Dec. 7, 1971 [73] Assignee Fujisawa Pharmaceutical Co.,Ltd.

Osaka, Japan [32] Priorities Apr. 28, 1967 [33] Japan [31] 42/27625;

Mar. 9, 1968, Japan, No. 43115528; Mar. 9, 1968, Japan, No. 43/15529[54] DllBENZOTHIAZEPlNE DERIVATHVES 9 Claims, N0 Drawings [52] 11.8. Cl260/327, 260/247. 1 260/268, 260/293.4, 260/307, 260/310, 260/313-.l,424/248, 424/267, 424/272, 424/273, 424/274, 424/275 [51 llnt. CI ..A6lk27/00, C07d 93/42 [50] Field of Search 260/327 B 56] Reierences CitedUNITED STATES PATENTS 3,188,322 6/1965 Yale et al 260/327 FOREIGNPATENTS 1,385,360 12/1964 France 260/327 1,385,360 11/1966 France260/327 Primary Examiner1lenry R. Jiles Assistant Examiner-C. M. ShurkoAttorneys-John J. Hart, Charles E. Baxley, Frank M. Nolan and Thomas E.Tate wines ens l v q nv s a,

wherein each ofX and X is hydrogen or halogen; R is alkyl, haloalkyl,aralkyl or alkyl substituted with R in which R is amino, alkylamino,dialkylamino; and R is hydrogen, alkyl, haloalkyl, aralkyl or alkylsubstituted with R in which R is the same meaning as defined above,provided that either R or R, should be alkyl substituted with R Thesecompounds possess potent antireserpinelike activity which makes themuseful as an antidepressant.

DIBENZOTHIAZEPINE DERIVATIVES This invention relates to newdibenzothiazepine derivatives and their salts, as well as the productionof the same.

In accordance with the invention there is provided a new compound of theformula (I):

wherein each of X, and X is hydrogen or halogen; R, is alkyl, haloalkyl,aralkyl or alkyl substituted with R in which R, is amino, alkylamino,dialkylamino or saturated 5 to 7 membered N-heterocyclic radical: and Ris hydrogen, alkyl, haloalkyl, aralkyl or alkyl substituted with R inwhich R, is the same meaning as defined above, provided that either R,or R should be alkyl substituted with R or salt thereof.

In the above and subsequent description and claims of this invention,the term halogen" and the halogen atom in the term haloalkyl andhaloaryl" means fluorine, chlorine, bromine and iodine; the term alkyl"means a straight, branched or cyclic monovalent hydrocarbon having oneto six carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl, hexyl, cyclohexyl and the like; the alkyl radical inthe term haloalkyl," alkylamino," dialkylamino," alkyl substituted withR alkylimino" and hydroxyalkylimino" means a straight or branchedmonovalent hydrocarbon having one to six carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like;the term aralkyl" and the aralkyl radical in the term aralkylimino" meana monocyclic aryl monovalent hydrocarbon such as benzyl, phenethyl,a-menthylbenzyl, phenylpropyl, tolylmethyl, xylylmethyl and the like;the term aryl" and the aryl radical in the term haloaryl and arylimino"mean a monocyclic aromatic monovalent hydrocarbon such as phenyl, tolyl,xylyl and the like; the term a saturated 5 to 7 membered N-heterocyclicradical" means nitrogeneous monocyclic one which may be substituted withhydroxy and either aryl or haloaryl, and whose carbon chain may beinterrupted or not with oxo, imino, alkylmino, hydroxyalkylimino,aralkylimino or arylimino, such as l-pyrrolidinyl, l-pyrazolidinyl,l-oxazolidinyl, piperidino, l-piperazinyl, 4-methyl(or ethyl)-l-piperazinyl, 4-hydroxyethyl (or hydroxymethyl)-l-piperazinyl,4-benzyl-l-piperazinyl, 4-phenyl-l-piperazinyl,4-hydroxy-4-phenylpiperidino, 4-hydroxy-4-(4 chlorophenyl)piperidino,morpholino, l-azepinyl and the like.

Among salts of the dibenzothiazepine derivatives (1), there are includeda nontoxic acid addition salts as well as a quarternary ammonium saltsthereof. Examples of the nontoxic acid addition salts are the salts withan inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuricacid and the like, and with an organic acid such as maleic acid,tartaric acid, citric acid, succinic acid, picric acid,p-toluenesulfonic acid and the like. Also, as to the quarternaryammonium salts, there are exemplified the salts with alkyl halide suchas methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethylbromide, ethyl iodide, propyl iodide and the like, and with aralkylhalide such as benzyl chloride, benzyl bromide, phenethyl bromide andthe like.

The compound (I) of this invention is novel and of great worthmedically. More particularly, it possesses, for instance, a potentreserpine-antagonism and is useful as an antidepressant.

The compound (I) of this invention may be administered orally andparenterally in the therapeutical use. The pharmaceutically usefulcompositions containing the compound (I) together with a significantamount of a nontoxic solid or liquid carrier are also included within ascope of this invention. In such compositions are included solidcompositions such as tablets, pills, dispersible powders and granules,and

liquid solutions such as injectable solutions, orally administrablesolutions and suspensions.

In solid compositions one or more of the active compounds is or areadmixed with an inert diluent such as potato starch, lactose, calciumphosphate and further additional substances, if needed, such as alublicant, e.g. magnesium stearate and the like; a binder, e.g. gelatinand the like; and a-disintegrator, e.g. cellulose calcium glycolate andthe like. In solid compositions, are included capsules of absorbablematerial such as gelatin containing one or more active compounds with orwithout the addition of diluents or excipients, and also suppositoriesfor rectal administration containing one or more active compounds forwhich bases are exemplified with cacao butter, glycerogelation,polyvinylalcohol, vegetable hardened oil, etc.

The compound (I) of this invention may be prepared basically byalkylation of an appropriate dibenzothiazepine compound in which thereis replaceable hydrogen atom at the Sthe or 1 lth position ofdibenzothiazepine: ring, or by ring-closing reaction of an appropriateamino benzylthiophenol derivative.

More concretely, the compound (.I) may be prepared by treating acompound of the formula (III):

wherein X, and X are the same meaning as defined in the formula (l), R,is hydrogen, alkyl, haloalkyl, aralkyl or alkyl substituted with R and Ris hydrogen, alkyl, haloalkyl, aralkyl or alkyl substituted with R inwhich R, is the same meaning as defined in the formula (I), providedthat at least one of R and R, should be hydrogen.

with an organic lithium compound and] an alkylating agent, or with analkylating agent in the presence of an alkaline condensing agent, and,if needed, treating the resultant compound (I) of R, or R beinghaloalkyl with an amine of the formula: R I-l wherein R is the samemeaning as described above. Alternatively, the compound (I) may also beobtained by ringclosing with heating a compound of the formula III):

S Xi \J 2 r IH X/ R2 (III) wherein X,, X R, and R are the same meaningas defined above, and X is an acid residue.

The compound (II) and (III) as the starting compound include known andunknown ones, and the compound (Ill) may be obtained, for instance, bythe reaction of an 2- aminothiophenol derivative and a Z-halobenzylhalide derivative and also the compound (Il) may be prepared byring-closing reaction of an appropriate Z-aminobenzylthiophenolderivative.

The reaction for the production of the compound (I) of this inventionwill each herein after illustrated in detail.

ALKYLATION l. C-Alkylation This alkylation is substantially concernedwith the replacement of the hydrogen atom at l lth position of thecompound (II) with a group ofR wherein R, has the same definition withR, of the formula (I). The reaction is carried out by treating thecompound (ll) wherein R is hydrogen, with an organic lithium compoundand an alkylating agent to give the desired compound (I).

As an organic lithium compound to be used, there are included an alkyllithium (e.g. methyl, ethyl, propyl, isopropyl, butyl or isobutyllithium and the like), aryl lithium (e.g. phenyl, tolyl, xylyl ornaphthyl lithium and the like) and aralkyl lithium (e.g. benzyl,phenethyl, phenylpropyl or tolymethyl lithium and the like).

The alkylating agent as used herein are a reactive ester of alkylalcohol (or haloalkyl, aralkyl or k -alkyl alcohol) which isrepresentable by the formula of R X, wherein R, has the same meaningwith R, of the formula (I) and X is an acid residue. k -alkyl" as usedherein and hereinafter means alkyl substituted with R Examples of thealkylating agent are alkyl, haloalkyl, aralkyl and R -alkylhalide(chloride, bromide and iodide); alkyl, haloalkyl, aralkyl and R-alkyl p-toluenesulfonate; alkyl, haloalkyl, aralkyl and R -alkylsulfonate and the like, among which the halide can be preferably used inthis reaction.

When using of haloalkyl halide, it is desired to select one having twodifferent halogens such as chloroalkyl bromide, chloroalkyl iodide orbromoalkyl iodide.

The reaction is generally carried out in a solvent such as ether,n-hexane, benzene or other inert solvent, and at room temperature orapproximately at the boiling point of solvent to be used, though theyare not particularly limited and depend on the kinds of the startingcompound and other reagent to be applied.

Furthermore, as a reaction mechanism in this reaction, it is consideredthat the compound (II) as the starting compound is firstly reacted withan organic lithium compound, thereby to substitute a hydrogen atom inmethylene part at the l lth position of the compound (II) with lithium,and then the lithium substitution product is reacted with an alkylatingagent, thereby to substitute lithium with the alkyl part of thealkylating agent. Accordingly, it is preferable to treat firstly thecompound (II) with an organic lithium compound and then the resultantmixture with an alkylating agent.

2. N-Alkylation This alkylation is substantially concerned with thereplacement of the hydrogen atom attached to nitrogen atom at the fifthposition of the compound (II), with a group of R wherein R,, is the samemeaning as defined above.

It is conducted by treating the compound (II) wherein R, is hydrogen,with an alkylating agent in the presence of an alkaline condensing agentto give the desired compound (I).

A few examples of the alkaline condensing agent to be used herein arealkali metal (e.g. sodium or potassium), alkaline earth metal (e.g.magnesium, calcium or barium), or their hydroxide, hydride, alkoxide orcarbonate. As the alkylating agent in this reaction, it can be employedin the substantially same one as described in the C-alkylation. Thereaction is usually conducted in a solvent such as liquid ammonia,dimethylformamide, dimethylsulfoxide, methanol, ethanol or any otherinert solvent, though it is nonlimitative. These solvents may beemployed in a mixture each other. The reaction temperature varies inaccordance with the kinds of the starting compound (II), the alkalinecondensing agent and a solvent to be used. The reaction is generallyeffected approximately at the boiling point of the solvent to be used,but when using dimethylformamide, liquid ammonia or the like, it may beeffected at lower temperature.

When the compound (I) of R, or R being haloalkyl is produced in theabove-mentioned alkylations, it can be converted into the correspondingcompound (I) of R, or R being R -alkyl by treatment with an amine of theformula:

R,H wherein R, is the same meaning as defined in the formula The aminemeans ammonia, mono alkylamine, dialkylamine or a saturated to 7membered N-heterocyclic compound.

The reaction may be carried out in a solvent such as benzene, toluene,xylene, chloroform and any other inert solvent. When the amine used isliquid, it may act as a solvent.

RING-CLOSURE This ring-closing reaction may be conducted by heating thecompound (III) to obtain the object compound (I).

The acid residue in the definition X, of the compound (Ill) means anresidue of an acid such as hydrohalogenic acid (e.g. hydrochloric acid,hydrobromic acid or hydroiodic acid), sulfuric acid, alkylsulfuric acid,p-toluenesulfonic acid and the like. The ring-closing reaction mayadvantageously be achieved in the presence of an alkaline condensingagent. As an alkaline condensing agent to be used herein, there is thesame agent as employed in the N-alkylation.

The reaction is ordinally carried out in a solvent such as pyridine,picoline, dimethylaniline, trimethylamine, triethylamine,dimethylformamide and the like. When the starting compound (Ill)possesses halogen as an acid residue, the reaction may be accelerated bythe addition of a dehydrohalogenation catalyst such as cupper powder orthe like. It is generally effected at a neighborhood of boiling point ofa solvent to be used. If it is desired to carry out the reaction athigher temperature, a solvent having high-boiling point is to be appliedfor.

Though the object compound (I) may be prepared by any reaction asmentioned above, it is preferred, for the purpose of economicalproduction of the compound (I), to select a suitable one from the abovereactions or use a combination thereof, depending upon the kinds of thehalogen atom on the benzene ring as well as the substituent(s) at thefifth and/or 1 lth position of the compound (I) to be desired. Forinstance, the compound (I) of R, being R -,-alkyl can advantageously beobtained by the C-alkylation of the starting compound (II) wherein R ishydrogen, with an alkyl halide having a substituent of R or theC-alkylation of said compound (I) with haloalkyl halide and then theamination of the resultant product. And also, when the compound (II) ofX, and/or X, being bromine or iodine is used in the C-alkylation, thereis a possibility of said halogen being substituted with lithium duringthis reaction. Accordingly, it is proposed to employ the N- alkylationor ring-closing reaction as explained hereinabove as an advantageousmethod for preparing the object compound (I) of X and/or X being bromineor iodine.

Thus obtained compound (I) may be converted into the corresponding saltby treatment with an organic or inorganic acid or with alkyl or aralkylhalide.

The following specific examples illustrate the production ofrepresentative compounds of this invention.

To a floating solution of lithium metal (4l0 mg.) in ether, was addedbromobenzene (4.7 g.) and heated under reflux till the floating lithiummetal disappeared. The ether solution of phenyl lithium thus prepared,was dropwise added with a solution of 5-methyl-5,l l-dihydrodibenzo[b,e][ [,4] thiazepine (6.1 g.) in ether (60 cc.) and then themixture was stirred at room temperature for 3 hours. To this mixture wasadded 2- dimethylaminoethyl chloride (6.0 g.) and heated under refluxfor 5 hours. After cooling, the remaining lithium was filtered off. Theether layer was washed with water and further extracted with a 10percent hydrochloric acid aqueous solution. The hydrochloric acidextract was neutralized with a 10 percent sodium hydroxide aqueoussolution and the precipitating oil was extracted with chloroform. Thechloroform extract was condensed and thus obtained oily substance wasdistilled under reduced pressure to obtain an oil (25 g.) as adistillate at l80l82 C./0.9 mm. Hg. This oil was treated according tothe conventional method for preparing an acid addition salt to obtainS-methyl-l I-(Z-dimethylaminoethyl )-5,l l-dihydro dibenzo[b,e]l l,4]thiazepine maleate having m.p. 170l 72 C. (decomp.)

Analysis calculated for C.,.H,,N,S-C.H.0.

C 63.75, H 6.32. N 6.72. S 7.72, Found: C 63.28, H 6.28, N 6.59, S 7.59.

EXAMPLE I (2) CH; CH CH CH B/ S S To a ether solution of phenyl lithiumprepared by the reaction of lithium metal (0.41 g.) and bromobenzene(4.7 g.) according to the conventional method, was dropwise added 5-methyl-5,11-dihydro dibenzo[b,e][1,4]thiazepine (6.1 g.) in ether (60c.c), after which the mixture was stirred at room temperature for 3hours. To this mixture was added 3- dimethylaminopropyl chloride (6.0g.) and the reaction mixture was heated under reflux for 5 hours.

This reaction mixture was treated in the same manner as described inexample l(l) to obtain an oil (2.5 g.) of 5- methyl-l l(B-dimethylaminopropyD-S,1 l-dihydro dibenzo[b,eH1,4]thiazepine (2.5 g.).

Analysis calculated for C,.,H,.N,S

N 8.97, S 10.24, Found: N 8.87, 5 10.20.

Found: C 71.04, H 7.l9. N 8.0].

S-Methyl-l l( 3-morpholinopropyl)-5,l l-dihydro dibenzo[b,e][l,4]thiazepine, an oil.

Analysis calculated for C,.H N,S

S 9.05. Found: C 7l.40, H 7.45. N 3J5.

2-Chloro-5-methyl-l l-(2-dimethylaminoethyl)-5,l l-dihydro dibenzo[b,e][l ,4]thiazepine, a yellowish viscous oil,

Analysis calculated for C M ,lfiSCl C 64.94. H 6.5 l N 8.39. S 9.63. CIl0.65.

C 65.04. H 6.54, N 8.38, S 9.79.

CI I080.

Found:

2-chloro-5-methyl-l l( 3-dimethylaminopropyl )-5 .l l-dihydrodibenzo[b,e][ 1,4]thiazepine, a yellow oil.

Analysis calculated for C H b.e|23N,SCl

C 65.78. H 6.68. N 8.07, S 9.29. Cl 10.22. Found: C 65.80, H 6.59. N8.20,

Cl 9.98. S-Methyl-l l[3-( l-pyrrolidinyl)propyl]-5 ,l l-dihydro dibenzo[[b,3[ 1.4 lthiazepine, a reddish yellow oil.

S l @l qn H3 To an ether solution of phenyl lithium prepared from phenylbromide (2.5 g.). lithium (220 mg.) and absolute ether (22 cc), wasadded dropwise 5-methyl-5,l l-dihydro dibenzo[b,e1,4]thiazepine (2.0 g.)in benzene (22 cc). The mixture was stirred at room temperature for 3hours and then added with l-bromo-3-chloropropane (7.5 g.). The reactionmixture was stirred at 50 C. for 3.5 hours and cooled, after which theremaining lithium was filtered off.

The reaction mixture was washed with water and then a 10 percenthydrochloric acid aqueous solution, and dried over anhydrous mangesiumsulfate. The solvent was distilled off to obtain an oil, which wassubjected to chromatograph using a column packed with almina, wherepetroleum ether and then n-hexane were used as developing solvents andchloroform was applied as an eluting solvent. The eluting chloroform wascondensed to obtain a yellow oil (2.0 g.).

Thus obtained oil (2.0 g.) was allowed to react with methylpiperazine(20 cc.) at C. for 17 hours. The reaction mixture was added with waterand extracted with a mixture of benzene and ether. The extract waswashed with water several times and further a 10 percent hydrochloricacid aqueous solution. and neutralized with a cone. sodium hydroxidesolution and then extracted with chloroform. The chloroform layer wassubjected to chromatograph using a column packed with almina in the samemanner as above to obtain an oil. This oil was distilled in an oil bathunder reduced pressure to obtain 5-methyl-1 l-[3-(4-methylpiperazinyl)propyl]-5, l l-dihydro dibenzo[b,e [l,4]thiazepine as a distillate under0.1-0.2 mm. Hg at 240-260 C.

Analysis calculated for C H N S N HA4. S 8.7l. C 72.l3. H 8.06. N

Analysis calculated for C H NJ S QHJL C 60.09. H 6.2l. N 7.0L

Found: c 60.50. H 6.23, N 7.05.

According to a similar manner to example 2( 1) described above, thefollowing compound was obtained.

S-Methyl-l 1-[2-[4-(2-hydroxyethyl)piperazinyl ]ethyl]- 5,l l-dihydrodibenzo[b,e" l,4]thiazepine, a reddish yellow viscous oil.

Analysis caLculated for C,,H,,N,SO

C 68.90. H 7.62. N l0.96, S 8.35.

C 68.56. H 7.5l, N l0.59, S 8.26.

Found:

lts hydrochloride was melted at 238-240 C.(decomp.

Analysis calculated for C,,l*l,,N SO-2HCl C 57.89, H 6.85, N 9.2], S7.02,

C 58.23, H 6.74, N 9.36,

EXAMPLE 2( 2) Found:

CHzCHzCHzCl A similar manner according to example 2-(2) was occupiedusing xylene solution of 4-hydroxy-4-phenyl-piperidine, 5- Methyl-ll-[3-(4-hydroxy-4-phenylpiperidinyl)propyl]-5,l 1- dihydro dibenzo[b,e][ l,4]thiazepine was obtained as an oil.

Infra-red Spectrum:

3400 cut. (OH) 2800 cm. (-N

670 cm. (mono substituted benzene) Nuclear Magnetic Resonance Spectrum:

l,4]thiazepine (2.1 g.) in absolute dimethylformamide c.c.), wasdropwise added, under ice-cooling, to a solution of sodium hydride (960mg.) in absolute dimethylformamide (20 cc). The reaction was carried outexothermically and the color of the reaction mixture changed to reddishbrown. This reaction mixture was stirred at room temperature for an hourand then at 50 C. for an hour. To this mixture was added a solution ofN,N-dimethylaminopropyl chloride (1.2 g.) in dimethylformamide (10 c.c.)and the mixture was stirred at room temperature and then at 50 C. for anhour respectively. After cooling, the reaction mixture was poured intowater and extracted with ether. The ether extract was washed with waterand extracted with a 10 percent hydrochloric acid aqueous solution. Thehydrochloric acid extract was cooled and neutralized with a 10 percentsodium hydroxide aqueous solution. The precipitating oil was extractedwith ether and the ether extract was dried, after which the solvent wasdistilled off to obtain an oil (0.5 g.) of 5-( 3-dimethylaminopropyl)-llmethyl-5,1 l-dihydro dibenzo[b,e 1,4]thiazepine.

This oily substance was treated according to the conventional method forpreparing an acid addition salt to obtain crystals of5-(3-dimethylaminopropyl)-1 l-methyl-5,l ldihydro dibenzo[b,e1,4]thiazepine oxalate having m.p. 139-l43 C. (decomp.).

Analysis calculated for C rs u s s s a C 62.66, H 6.5L N 6.96, S 7.97.

Found: C 62.77, H 6.72, N 6.93, S 8.12.

EXAMPLE 4 CH3 CH3 NH, Br N 1.52 PPM (doublet, CH on the (a) structure)1.57 PPM (doublet,-CH;, on the (b) structure) 4.30 PPM (quartet. thehydrogen at the llthe position on the (a) structure) 4.75 PPM (quartet,the hydrogen at the 1 lthe position on the (b) structure) We claim:

1. A compound of the formula:

H CH

wherein each of X, and X is hydrogen or halogen; R, is alkyl, haloalkylor alkyl substituted with R in which R, is amino, alkylamino ordialkylamino; and R is hydrogen, alkyl, haloalkyl or alkyl substitutedwith R in which R, is the same meaning as defined above, provided thateither R, or R should be alkyl S substituted with R wherein the alkylgroup has from one to six carbon atoms.

2. The compound according to claim 1, in which R, is alkyl substitutedwith dialkylamino, R is alkyl and each of X, and

X, is hydrogen, i.e., 5-alkyl-ll-(dialkaminoalkyl)-5,ll- 1O 5. Thecompound according to claim 1, in which R, is alkyl substituted withdialkylamino, R is alkyl, X, is hydrogen and X is 2-halo, i.e.,2-halo-5-alkyl-1l,(dialkylaminoalkyl)-5,l ldihydro dibenzo[b,e][1,4]thiazepine.

6. The compound according to claim 5 in which R, is dimethylaminoethyl,R, is methyl, X, is hydrogen and X is 2- chloro i.e., 2'chloroS-methyl-l l-(2dimethylaminoethyl)- 5,l l-dihydro dibenzo[b,e][1,4]thiazepine.

7. The compound according to claim 5, in which R, isdimethylaminopropyl, R is methyl, X, is hydrogen and X is 2-chloro,i.e., 2-chloro-5-methyl-l l-(-dimethylaminopropyl)- 5,1 l-dihydrodibenzo[b,e][ 1,4]thiazepine.

8. The compound according to claim 1, in which R, is alkyl, R, is alkylsubstituted with dialkylamino and each X, and X is hydrogen, i.e.,S-(dialkylaminoalkyll-l l-alkyl-5,l l-dihydro dibenzo[b,e][1,4]thiazepine.

9. The compound according to claim 8, in which R, is methyl, R isdimethylaminopropyl and each of X, and X is hydrogen, i.e.,5-(3-dimethylaminopropyl ll-methyl-5,l ldihydro dibenzo[ [b,3][1,4]thiazepine.

3,625,974 1mm] December Inventor) Suminori Umio and Ikuo Ueda It iscertified that error appears in the abovc-idcntificd patent and thatsaid Letters Patent are hereby corrected as shown below:

In the Abstract, the structural formula E X X should read X -X Column 1,line 36, "q-menthylbenzyl" should read --u-methyl benzyl--; line 45,"alkylmino" should read alkylimino-; line 53, delete "a" before"nontoxic., Column 2, line 6, "lublicant" should read --lubricant-; line19, "Sthe" should read 5th--; line 55, "compound" should read-compounds--; line 64, after "each" insert be-. Column 3, line 19, "of"should read --a,- line 57, after "mixture" insert with. Column 5, lines53, 61 and 69, the spaces in the formulas should be closed, making theformulas read respectively: C2 H2 ON2S; C H ON S; C H2 N2SCl. Column 6,line 4, the

formula "C H b,e]23N SCl" should read --C H N SCl-;

line 10, "Cl 9.98" should follow "59.411." in line 9; line 49, "almina"should read --alumina-; line 61, "almina" should read -alumina--; line75, space in the formula should be closed, making it read C H N S -C H OColumn 7,

line 16, space in formula should be closed, making it read -C H NSO'2HCl-; line 42, after "piperidine", the comma should be replaced byColumn 8, lines 25 and 26, the formula should be on one line and read -CH N S-C H D Column 10, line 6, insert a dash between "chloro" and ".5".

L .9 Signed and sealed this 28th day of November 1972.

(SEAL) Attest:

EDWARD mmsrcmsmm. ROBhRT sorrscm rz ttesting Officer Commissioner 0.stents

2. The compound according to claim 1, in which R1 is alkyl substitutedwith dialkylamino, R2 is alkyl and each of X1 and X2 is hydrogen, i.e.,5-alkyl-11-(dialkaminoalkyl)-5,11-dihydro dibenzo( b,e)(1,4)thiazepine.3. The compound according to claim 2, in which R1 is dimethylaminoethyl,R2 is methyl and each of X1 and X2 is hydrogen, i.e.,5-methyl-11-(2-dimethylaminoethyl)-5,11-dihydro dibenzo(b,e)(1,4)thiazepine.
 4. The compound according to claim 2, in which R1is dimethylaminopropyl, R2 is methyl and each of X1 and X2 is hydrogen,i.e., 5-methyl-11-(3-dimethylaminopropyl)-5,11-dihydro dibenzo(b,e)(1,4)thiazepine.
 5. The compound according to claim 1, in which R1is alkyl substituted with dialkylamino, R2 is alkyl, X1 is hydrogen andX2 is 2-halo, i.e., 2-halo-5-alkyl-11,(dialkylaminoalkyl)-5,11-dihydrodibenzo( b,e)(1,4)thiazepine.
 6. The compound according to claim 5 inwhich R1 is dimethylaminoethyl, R2 is methyl, X1 is hydrogen and X2 is2-chloro i.e., 2-chloro 5-methyl-11-(2dimethylaminoethyl)-5,11-dihydrodibenzo( b,e)(1,4)thiazepine.
 7. The compound according to claim 5, inwhich R1 is dimethylaminopropyl, R2 is methyl, X1 is hydrogen and X2 is2-chloro, i.e., 2-chloro-5-methyl-11-(-dimethylaminopropyl)-5,11-dihydrodibenzo(b,e)(1,4)thiazepine.
 8. The compound according to claim 1, inwhich R1 is alkyl, R2 is alkyl substituted with dialkylamino and each X1and X2 is hydrogen, i.e., 5-(dialkylaminoalkyl)-11-alkyl-5,11-dihydrodibenzo( b,e)(1,4)thiazepine.
 9. The compound according to claim 8, inwhich R1 is methyl, R2 is dimethylaminopropyl and each of X1 and X2 ishydrogen, i.e., 5-(3-dimethylaminopropyl 11-methyl-5,11-dihydrodibenzo((b,3)(1, 4)thiazepine.